tbuckley/cabot-search huggingface dataset:
Long covid: nearly half of doctors affected can no longer work full time, finds survey
Authors: Adele Waters
Journal: BMJ (2023)

Long covid: nearly half of doctors affected can no longer work full time, finds survey Adele WatersAlmost one in five doctors (18%) with long covid who responded to a survey said that they were no longer able to work, and fewer than one in three (31%) were working full time, compared with more than half (57%) before the onset of their covid illness.1
Chronic SIRT1 supplementation in diabetic mice improves endothelial function by suppressing oxidative stress
Authors: Kangmin Yang, Srividya Velagapudi, Alexander Akhmedov, Simon Kraler, Tetiana Lapikova-Bryhinska, Martin O Schmiady, Xiaoping Wu, Leiluo Geng, Giovanni G Camici, Aimin Xu, Thomas F Lüscher
Journal: Cardiovascular Research (2023)

Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation to alleviate endothelial and vascular dysfunction in diabetic mice (db/db).Left internal mammary arteries obtained from patients undergoing coronary artery bypass grafting with or without a diagnosis of diabetes were assayed for SIRT1 protein levels. Twelve-week-old male db/db mice and db/+ controls were treated with vehicle or rmSIRT1 intraperitoneally for 4 weeks, after which carotid artery pulse wave velocity (PWV) and energy expenditure/activity were assessed by ultrasound and metabolic cages, respectively. Aorta, carotid, and mesenteric arteries were isolated to determine endothelial and vascular function using the myograph system.Arteries obtained from diabetic patients had significantly lower levels of SIRT1 relative to non-diabetics. In line, aortic SIRT1 levels were reduced in db/db mice compared to db/+ mice, while rmSIRT1 supplementation restored SIRT1 levels. Mice receiving rmSIRT1 supplementation displayed increased physical activity and improved vascular compliance as reflected by reduced PWV and attenuated collagen deposition. Aorta of rmSIRT1-treated mice exhibited increased endothelial nitric oxide (eNOS) activity, while endothelium-dependent contractions of their carotid arteries were significantly decreased, with mesenteric resistance arteries showing preserved hyperpolarization. Ex vivo incubation with reactive oxygen species (ROS) scavenger Tiron and NADPH oxidase inhibitor apocynin revealed that rmSIRT1 leads to preserved vascular function by suppressing NADPH oxidase (NOX)-related ROS synthesis. Chronic rmSIRT1 treatment resulted in reduced expression of both NOX1 and NOX4, in line with a reduction in aortic protein carbonylation and plasma nitrotyrosine levels.In diabetic conditions, arterial SIRT1 levels are significantly reduced. Chronic rmSIRT1 supplementation improves endothelial function and vascular compliance by enhancing eNOS activity and suppressing NOX-related oxidative stress. Thus, SIRT1 supplementation may represent novel therapeutic strategy to prevent diabetic vascular disease.
Expression Profiling Reveals Novel Pathways in the Transformation of Melanocytes to Melanomas
Authors: Keith Hoek, David L. Rimm, Kenneth R. Williams, Hongyu Zhao, Stephan Ariyan, Aiping Lin, Harriet M. Kluger, Aaron J. Berger, Elaine Cheng, E. Sergio Trombetta, Terence Wu, Michio Niinobe, Kazuaki Yoshikawa, Gregory E. Hannigan, Ruth Halaban
Journal: Cancer Research (2004)

Abstract Affymetrix and spotted oligonucleotide microarrays were used to assess global differential gene expression comparing normal human melanocytes with six independent melanoma cell strains from advanced lesions. The data, validated at the protein level for selected genes, confirmed the overexpression in melanoma cells relative to normal melanocytes of several genes in the growth factor/receptor family that confer growth advantage and metastasis. In addition, novel pathways and patterns of associated expression in melanoma cells not reported before emerged, including the following: (a) activation of the NOTCH pathway; (b) increased Twist expression and altered expression of additional transcriptional regulators implicated in embryonic development and epidermal/mesenchymal transition; (c) coordinated activation of cancer/testis antigens; (d) coordinated down-regulation of several immune modulation genes, in particular in the IFN pathways; (e) down-regulation of several genes implicated in membrane trafficking events; and (f) down-regulation of growth suppressors, such as the Prader-Willi gene NECDIN, whose function was confirmed by overexpression of ectopic Flag-necdin. Validation of differential expression using melanoma tissue microarrays showed that reduced ubiquitin COOH-terminal esterase L1 in primary melanoma is associated with worse outcome and that increased expression of the basic helix-loop-helix protein Twist is associated with worse outcome. Some differentially expressed genes reside on chromosomal regions displaying common loss or gain in melanomas or are known to be regulated by CpG promoter methylation. These results provide a comprehensive view of changes in advanced melanoma relative to normal melanocytes and reveal new targets that can be used in assessing prognosis, staging, and therapy of melanoma patients.
The Evolutionary History of <i>Drosophila simulans</i> Y Chromosomes Reveals Molecular Signatures of Resistance to Sex Ratio Meiotic Drive
Authors: Cécile Courret, David Ogereau, Clément Gilbert, Amanda M Larracuente, Catherine Montchamp-Moreau
Journal: Molecular Biology and Evolution (2023)

Abstract The recent evolutionary history of the Y chromosome in Drosophila simulans, a worldwide species of Afrotropical origin, is closely linked to that of X-linked meiotic drivers (Paris system). The spread of the Paris drivers in natural populations has elicited the selection of drive-resistant Y chromosomes. To infer the evolutionary history of the Y chromosome in relation to the Paris drive, we sequenced 21 iso-Y lines, each carrying a Y chromosome from a different location. Among them, 13 lines carry a Y chromosome that is able to counteract the effect of the drivers. Despite their very different geographical origins, all sensitive Y's are highly similar, suggesting that they share a recent common ancestor. The resistant Y chromosomes are more divergent and segregate in four distinct clusters. The phylogeny of the Y chromosome confirms that the resistant lineage predates the emergence of Paris drive. The ancestry of the resistant lineage is further supported by the examination of Y-linked sequences in the sister species of D. simulans, Drosophila sechellia and Drosophila mauritiana. We also characterized the variation in repeat content among Y chromosomes and identified multiple simple satellites associated with resistance. Altogether, the molecular polymorphism allows us to infer the demographic and evolutionary history of the Y chromosome and provides new insights on the genetic basis of resistance.
Healthcare experiences among patients with hidradenitis suppurativa: a qualitative study
Authors: Yacine Sow, Nicole Salame, Meron R Siira, Nyla Flowers, Amit Garg, Rachel E Patzer, Dio Kavalieratos, Kimberly A Curseen, Suephy C Chen, Lauren A V Orenstein
Journal: British Journal of Dermatology (2023)

In this qualitative study, 21 adults living with hidradenitis suppurativa (HS) were interviewed about their healthcare experiences. Participants detailed how delay in diagnosis, lack of provider knowledge, inadequate pain management, poor access to care and stigmatization negatively affected their interactions with the healthcare system. Improving disease knowledge among providers, proactively addressing HS-related pain and coordinating access to multidisciplinary care may improve healthcare experiences among individuals living with HS.
Effects of a More Selective Arteriovenous Fistula Strategy on Vascular Access Outcomes
Authors: Michael Allon, Alian Al-Balas, Carlton J. Young, Gary R. Cutter, Timmy Lee
Journal: Journal of the American Society of Nephrology (2023)

The optimal choice of vascular access for patients undergoing hemodialysis-arteriovenous fistula (AVF) or arteriovenous graft (AVG)-remains controversial. In a pragmatic observational study of 692 patients, the authors found that among patients who initiated hemodialysis with a central vein catheter (CVC), a strategy that maximized AVF placement resulted in a higher frequency of access procedures and greater access management costs for patients who initially received an AVF than an AVG. A more selective policy that avoided AVF placement if an AVF was predicted to be at high risk of failure resulted in a lower frequency of access procedures and access costs in patients receiving an AVF versus an AVG. These findings suggest that clinicians should be more selective in placing AVFs because this approach improves vascular access outcomes.
Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?
Authors: Christophe Corpechot, Sara Lemoinne, Pierre-Antoine Soret, Bettina Hansen, Gideon Hirschfield, Aliya Gulamhusein, Aldo J. Montano-Loza, Ellina Lytvyak, Albert Pares, Ignasi Olivas, John E. Eaton, Karim T. Osman, Christoph Schramm, Marcial Sebode, Ansgar W. Lohse, George Dalekos, Nikolaos Gatselis, Frederik Nevens, Nora Cazzagon, Alessandra Zago, Francesco Paolo Russo, Annarosa Floreani, Nadir Abbas, Palak Trivedi, Douglas Thorburn, Francesca Saffioti, Laszlo Barkai, Davide Roccarina, Vicenza Calvaruso, Anna Fichera, Adèle Delamarre, Natalia Sobenko, Alejandra Maria Villamil, Esli Medina-Morales, Alan Bonder, Vilas Patwardhan, Cristina Rigamonti, Marco Carbone, Pietro Invernizzi, Laura Cristoferi, Adriaan van der Meer, Rozanne de Veer, Ehud Zigmond, Eyal Yehezkel, Andreas E. Kremer, Ansgar Deibel, Tony Bruns, Karsten Große, Aaron Wetten, Jessica Katharine Dyson, David Jones, Jérôme Dumortier, Georges-Philippe Pageaux, Victor de Lédinghen, Olivier Chazouillères, Fabrice Carrat
Journal: Hepatology (2023)

Background and Aims: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. Approach and Results: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7–21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin &lt; 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7–59.9, p &lt; 0.001) when these 2 conditions were met. Conclusions: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.
The Effect of Frailty on the Efficacy and Safety of Intensive Blood Pressure Control: A Post Hoc Analysis of the SPRINT Trial
Authors: Zhiyan Wang, Xin Du, Chang Hua, Wenjie Li, Hao Zhang, Xinru Liu, Yufeng Wang, Chao Jiang, Jiakun Guo, Qiang Lv, Craig S. Anderson, Jianzeng Dong, Changsheng Ma
Journal: Circulation (2023)

Frailty is associated with an increased risk of all-cause death and cardiovascular events. However, it is uncertain whether frailty modifies the efficacy and safety of intensive blood pressure control.Data from SPRINT (Systolic Blood Pressure Intervention Trial) were used to construct a frailty index. Subgroup differences in intensive blood pressure control treatment effects and safety outcomes were measured on a relative and an absolute scale in patients with and without frailty (defined as a frailty index >0.21) using Cox proportional hazard models and generalized linear models, respectively. The primary outcome was a composite of myocardial infarction, acute coronary syndrome without myocardial infarction, stroke, heart failure, and cardiovascular death.A total of 9306 patients (mean age, 67.9±9.4 years), 2560 (26.7%) of whom had frailty, were included in our study. Over a median follow-up of 3.22 years, 561 primary outcomes were observed. Patients with frailty had a significantly higher risk of primary outcome in both the intensive and standard blood pressure control arms (adjusted hazard ratio, 2.10 [95% CI, 1.59-2.77] and 1.85 [95% CI, 1.46-2.35], respectively). Intensive treatment effects on primary and secondary outcomes were not significantly different on a relative scale (except for cardiovascular death [hazard ratio in patients with and without frailty, 0.91 (95% CI, 0.52-1.60) versus 0.30 (95% CI, 0.16-0.59), respectively; Pinteraction=0.01]) or absolute scale. There was no significant interaction between frailty and risks for serious adverse events with intensive treatment.Frailty status was a marker of high cardiovascular risk. Patients with frailty benefit similarly to other patients from intensive blood pressure control without an increased risk of serious adverse events.
SUSD2‐IL‐2 receptor interaction hinders antitumoral CD8<sup>+</sup> T‐cell activity: Implications for cancer immunotherapy
Authors: Pilar M. Moreno‐Sanchez, Andrea Scafidi, Ilaria Salvato
Journal: Allergy (2023)

The authors have nothing to disclose. The original article with the respective data information can be found at doi: 10.1038/s41590-022-01326-8.
Autoimmune Atrial Fibrillation
Authors: Ange Maguy, Yuvaraj Mahendran, Jean-Claude Tardif, David Busseuil, Jin Li
Journal: Circulation (2023)

Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF.Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization.A common autoantibody response against Kir3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. Kir3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K+ current, IKACh. Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-Kir3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of IKACh, both key mediators of AF. To establish a causal relationship, we developed a mouse model of Kir3.4 autoimmunity. Electrophysiological study in Kir3.4-immunized mice showed that Kir3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF.To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of Kir3.4 autoantibody-mediated AF.
Declining risk of heart failure hospitalization following first acute myocardial infarction in Scotland between 1991–2016
Authors: Kieran F. Docherty, Alice M. Jackson, Mark Macartney, Ross T. Campbell, Mark C. Petrie, Marc A. Pfeffer, John J.V. McMurray, Pardeep S. Jhund
Journal: European Journal of Heart Failure (2023)

Aim Mortality from acute myocardial infarction (AMI) has declined, increasing the pool of survivors at risk of later development of heart failure (HF). However, coronary reperfusion limits infarct size and secondary prevention therapies have improved. In light of these competing influences, we examined long‐term trends in the risk of HF hospitalization (HFH) following a first AMI occurring in Scotland over 25 years. Methods and results All patients in Scotland discharged alive after a first AMI between 1991 and 2015 were followed until a first HFH or death until the end of 2016 (minimum follow‐up 1 year, maximum 26 years). A total of 175 672 people with no prior history of HF were discharged alive after a first AMI during the period of study. A total of 21 445 (12.2%) patients had a first HFH during a median follow‐up of 6.7 years. Incidence of HFH (per 1000 person‐years) at 1 year following discharge from a first AMI decreased from 59.3 (95% confidence interval [CI] 54.2–64.7) in 1991 to 31.3 (95% CI 27.3–35.8) in 2015, with consistent trends seen for HF occurring within 5 and 10 years. Accounting for the competing risk of death, the adjusted risk of HFH at 1 year after discharge decreased by 53% (95% CI 45–60%), with similar decreases at 5 and 10 years. Conclusion The incidence of HFH following AMI in Scotland has decreased since 1991. These trends suggest that better treatment of AMI and secondary prevention are having an impact on the risk of HF at a population level.
Maternal microbiome disturbance induces deficits in the offspring’s behaviors: a systematic review and meta-analysis
Authors: Lucas Hassib, Cilene Lino de Oliveira, Guilherme Araujo Rouvier, Alexandre Kanashiro, Francisco Silveira Guimarães, Frederico Rogério Ferreira
Journal: Gut Microbes (2023)

Recent evidence has suggested that changes in maternal gut microbiota in early life may generate neurobiological consequences associated with psychiatric-related abnormalities. However, the number of studies on humans investigating this problem is limited, and preclinical findings sometimes conflict. Therefore, we run a meta-analysis to examine whether maternal microbiota disturbance (MMD) during neurodevelopment might affect the offspring during adulthood. We found thirteen studies, from a set of 459 records selected by strategy registered on PROSPERO (#289224), to target preclinical studies that evaluated the behavioral outcomes of the rodents generated by dams submitted to perinatal enteric microbiota perturbation. The analysis revealed a significant effect size (SMD = −0.51, 95% CI = −0.79 to −0.22, p < .001, T2 = 0.54, I2 = 79.85%), indicating that MMD might provoke behavioral impairments in the adult offspring. The MMD also induces a significant effect size for the reduction of the sociability behavior (SMD = −0.63, 95% CI = −1.18 to −0.07, p = 0.011, T2 = 0.30, I2 = 76.11%) and obsessive-compulsive-like behavior (SMD = −0.68, 95% CI = −0.01 to −1.36, p = 0.009, T2 = 0.25, I2 = 62.82%) parameters. The effect size was not significant or inconclusive for memory and anxiety-like behavior, or inconclusive for schizophrenia-like and depressive-like behavior. Therefore, experimental perinatal MMD is vertically transmitted to the offspring, negatively impacting behavioral parameters related to psychiatric disorders.
Efficacy and safety of early‐start deferiprone in infants and young children with transfusion‐dependent beta thalassemia: Evidence for iron shuttling to transferrin in a randomized, double‐blind, placebo‐controlled, clinical trial (<scp>START</scp>)
Authors: Mohsen S. Elalfy, Mona Hamdy, Amira Adly, Fatma S. E. Ebeid, Noemi Toiber Temin, Anna Rozova, David Lee, Caroline Fradette, Fernando Tricta
Journal: American Journal of Hematology (2023)

Abstract Children with transfusion‐dependent thalassemia (TDT) require regular blood transfusions that, without iron‐chelation therapy, lead to iron‐overload toxicities. Current practice delays chelation therapy (late‐start) until reaching iron overload (serum ferritin ≥1000 μg/L) to minimize risks of iron‐depletion. Deferiprone's distinct pharmacological properties, including iron‐shuttling to transferrin, may reduce risks of iron depletion during mild‐to‐moderate iron loads and iron overload/toxicity in children with TDT. The early‐start deferiprone (START) study evaluated the efficacy/safety of early‐start deferiprone in infants/young children with TDT. Sixty‐four infants/children recently diagnosed with beta‐thalassemia and serum ferritin (SF) between 200 and 600 μg/L were randomly assigned 1:1 to receive deferiprone or placebo for 12 months or until reaching SF‐threshold (≥1000 μg/L at two consecutive visits). Deferiprone was initiated at 25 mg/kg/day and increased to 50 mg/kg/day; some recipients' dosages increased to 75 mg/kg/day based on iron levels. The primary endpoint was the proportion of patients ≥SF‐threshold by month 12. Monthly transferrin saturation (TSAT) assessment evaluated iron‐shuttling. At baseline, there was no significant difference in mean age (deferiprone: 3.03 years, placebo: 2.63 years), SF (deferiprone: 513.8 μg/L, placebo: 451.7 μg/L), or TSAT (deferiprone: 47.98%, placebo: 43.43%) between groups. At month 12, there was no significant difference in growth or adverse event (AE) rates between groups. No deferiprone‐treated patients were iron‐depleted. At month 12, 66% of patients receiving deferiprone remained below SF threshold versus 39% of placebo ( p = .045). Deferiprone‐treated patients showed higher TSAT levels and reached ≥60% TSAT threshold faster. Early‐start deferiprone was well‐tolerated, not associated with iron depletion, and efficacious in reducing iron overload in infants/children with TDT. TSAT results provide the first clinical evidence of deferiprone shuttling iron to transferrin.